THERAPY MANAGEMENT GUIDE To help support your patients

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1 THERAPY MANAGEMENT GUIDE To help support your patients START with recommended dosing and administration MONITOR patients for appropriate treatment MANAGE adverse reactions with dose modifications SUPPORT eligible patients with financial and access resources INDICATIONS AND USAGE BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. IMPORTANT SAFETY INFORMATION The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full prescribing information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions. WARNINGS AND PRECAUTIONS New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuscc), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuscc/ka was 5.8 months. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI. Please see IMPORTANT SAFETY INFORMATION throughout and on page 7, and accompanying full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information.

2 Starting treatment with BRAFTOVI (encorafenib) + MEKTOVI (binimetinib) for patients with BRAF-mutant metastatic melanoma 1,2 BRAFTOVI + MEKTOVI recommended dosing 1,2 May be taken with or without food BRAFTOVI + MEKTOVI recommended administration 1,2 In case of vomiting, do not take an additional dose of BRAFTOVI or MEKTOVI; resume dosing with the next scheduled dose For patients with moderate or severe hepatic impairment, the recommended dose of MEKTOVI is 30 mg orally, taken twice daily START No refrigeration requirement; store at room temperature Uninterrupted dosing schedule Confirm the presence of BRAF V600E/K mutation by an FDA-approved test before treatment. BRAFTOVI 450 mg + MEKTOVI 45 mg Six 75-mg BRAFTOVI capsules and three 15-mg MEKTOVI tablets ~12 HOURS APART MEKTOVI 45 mg Three 15-mg MEKTOVI tablets Drug interactions Avoid coadministration/concomitant administration of strong or moderate CYP3A4 inhibitors (eg, grapefruit juice) and inducers with BRAFTOVI If concomitant use of a strong or moderate CYP3A4 inhibitor is unavoidable, reduce the BRAFTOVI dose to one-third of the dose prior to concurrent use of strong CYP3A4 inhibitors, or one-half of the dose prior to concurrent use of moderate CYP3A4 inhibitors BRAFTOVI is associated with dose-dependent QTc interval prolongation. Avoid coadministration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval Please see BRAFTOVI full Prescribing Information for complete information about drug interactions. Please see Section 2 of the full Prescribing Information for both BRAFTOVI and MEKTOVI for complete information on dosage and administration. Instruct patients not to take a missed dose of: 12 hour BRAFTOVI within 12 hours of the next dose 1st DOSE 2nd DOSE 6 MEKTOVI within 6 hours of the next dose hour Treatment with BRAFTOVI + MEKTOVI should be continued until disease progression or unacceptable toxicity. CYP3A4, cytochrome P450 3A4. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. Assess LVEF by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism. Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). 2 Please see IMPORTANT SAFETY INFORMATION throughout and on page 7.

3 Monitoring with BRAFTOVI (encorafenib) + MEKTOVI (binimetinib) for patients with BRAF-mutant metastatic melanoma 1,2 Guidance on monitoring patients during treatment for select ARs 1,2 Monitoring at treatment initiation and during treatment may help with adverse reaction management, allowing your patients to start and stay on treatment. BRAFTOVI + MEKTOVI dose adjustments and discontinuations due to ARs 1-3 BRAFTOVI + MEKTOVI dose adjustments due to ARs 3 Blood tests Echocardiogram/ MUGA scan Assessment of ophthalmologic symptoms 37 % BRAFTOVI + 48 % MEKTOVI VS vemurafenib Check prior to treatment Monitor during treatment LFT: Every month and as clinically indicated Creatinine with CPK: Periodically during treatment and as clinically indicated 1 month after initiation Every 2-3 months thereafter Assessed at each visit Perform ophthalmologic evaluation at regular intervals and for any visual disturbances The most common ARs ( 5%) for BRAFTOVI + MEKTOVI requiring a dose adjustment were nausea (8%), vomiting (7%), cardiomyopathy (6%), and serous retinopathy (6%) This includes a dose adjustment (including dose interruptions and reductions) of BRAFTOVI, MEKTOVI, or both ARs leading to discontinuation of BRAFTOVI + MEKTOVI 1,2 5 % discontinuations The most common ARs resulting in permanent due to ARs discontinuation were hemorrhage (2%) and headache (1%) MONITOR This analysis was not pre-specified and is descriptive in nature only BRAFTOVI + MEKTOVI recommended dose adjustments BRAFTOVI Starting dose 450 mg First reduction 300 mg Second reduction 200 mg If BRAFTOVI is permanently discontinued, then discontinue MEKTOVI MEKTOVI If unable to tolerate 200 mg QD, permanently discontinue BRAFTOVI. 6.9 MONTHS [95% CI: ] Median time to first dose interruption/reduction for patients receiving BRAFTOVI + MEKTOVI 3 This analysis was not pre-specified and is descriptive in nature only Starting dose 45 mg First reduction 30 mg If unable to tolerate 30 mg BID, permanently discontinue MEKTOVI. If MEKTOVI is withheld, reduce BRAFTOVI to a maximum dose of 300 mg once daily until MEKTOVI is resumed To learn more about the safety profile of BRAFTOVI + MEKTOVI visit braftovimektovi.com IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Perform ophthalmological evaluation for patientreported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals any time a patient reports visual disturbances. ARs, adverse reactions; BID, twice daily; CPK, creatine phosphokinase; LFT, liver function test; MUGA, multigated acquisition; QD, once daily. 3 Please see IMPORTANT SAFETY INFORMATION throughout and on page 7.

4 Managing ARs through dose modification with BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) for patients with BRAF-mutant metastatic melanoma 1,2 Select dose modification guidelines for BRAFTOVI and MEKTOVI 1,2 Reduce or withhold Maintain Permanently discontinue Adverse reaction Severity of adverse reaction* Dose modification for BRAFTOVI Dose modification for MEKTOVI Serous retinopathy Symptomatic serous retinopathy/retinal pigment epithelial detachment Reduce to 300 mg once daily until MEKTOVI is resumed If MEKTOVI dose is maintained, BRAFTOVI dose should not be modified Withhold for up to 10 days If improved and becomes asymptomatic, resume at same dose If not improved, resume at a lower dose level or permanently discontinue Ocular events Uveitis, including iritis and iridocyclitis Grades 1-3 Withhold for up to 6 weeks if Grades 1 or 2 does not respond to ocular therapy, or for Grade 3 uveitis If improved, resume at same or reduced dose If not improved, permanently discontinue Grade 4 Permanently discontinue Cardiomyopathy LVEF Asymptomatic absolute decrease in LVEF of greater than 10% from baseline that is below LLN Reduce to 300 mg once daily until MEKTOVI is resumed If MEKTOVI dose is maintained, BRAFTOVI dose should not be modified Withhold for up to 4 weeks and evaluate LVEF every 2 weeks. Resume at a reduced dose if the following are present: LVEF is ULN and Absolute decrease from baseline is 10% and Patient is asymptomatic If the LVEF does not recover within 4 weeks, permanently discontinue MANAGE Symptomatic congestive heart failure or absolute decrease in LVEF of greater than 20% from baseline that is also below LLN Reduce to 300 mg once daily Permanently discontinue Dose modifications are recommended to manage certain adverse reactions. Please see Section 2.3 of the full Prescribing Information for both BRAFTOVI and MEKTOVI for additional information Please see the full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for complete dose modification guidance IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. * National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version LLN, lower limit of normal; LVEF, left ventricular ejection fraction; ULN, upper limit of normal. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms. Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI. 4 Please see IMPORTANT SAFETY INFORMATION throughout and on page 7.

5 Managing ARs through dose modification with BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) for patients with BRAF-mutant metastatic melanoma 1,2 Select dose modification guidelines for BRAFTOVI and MEKTOVI 1,2 Reduce or withhold Maintain Permanently discontinue Adverse reaction Severity of adverse reaction* Dose modification for BRAFTOVI Dose modification for MEKTOVI Musculoskeletal Rhabdomyolysis or CPK elevations Grade 4 asymptomatic Any grade CPK elevation with symptoms or with renal impairment Reduce to 300 mg once daily until MEKTOVI is resumed If MEKTOVI dose is maintained, BRAFTOVI dose should not be modified Withhold dose for up to 4 weeks If improved to Grade 0 or 1, resume at a reduced dose If not resolved within 4 weeks, permanently discontinue Hepatotoxicity AST or ALT increased Grade 2 Maintain dose If no improvement within 4 weeks, withhold until improved to Grade 0 or 1 or to pretreatment/baseline levels, and then resume at the same dose Maintain dose If no improvement within 2 weeks, withhold until improved to Grade 0 or 1 or to pretreatment/ baseline levels, and then resume at the same dose Grades 3 or 4 Refer to Grade 3 or 4 guidance under Other ARs Other ARs, including hemorrhage Recurrent Grade 2 OR First occurrence of any Grade 3 First occurrence of any Grade 4 Withhold dose for up to 4 weeks If improved to Grade 0 or 1 or to pretreatment/baseline levels, resume at a reduced dose If no improvement, permanently discontinue Permanently discontinue or withhold for up to 4 weeks If improved to Grade 0 or 1 or to pretreatment/baseline levels, resume at a reduced dose If no improvement, permanently discontinue Recurrent Grade 3 Consider permanently discontinuing Recurrent Grade 4 Permanently discontinue *NCI CTCAE version ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase. For complete dose modification guidance, please see the full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI 5 Dose modification of BRAFTOVI when administered with MEKTOVI is not recommended for new primary cutaneous malignancies, ocular events other than uveitis, iritis, and iridocyclitis, interstitial lung disease/pneumonitis, cardiac dysfunction, CPK elevation, rhabdomyolysis, and venous thromboembolism. Dose modification of MEKTOVI when administered with BRAFTOVI is not recommended for the following adverse reactions: palmar-plantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS (CONT) Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. Please see Table 2 in Section 2.3 of the full Prescribing Information for BRAFTOVI for more information on adverse reactions that may require a dose adjustment or modification, such as: New primary malignancies QTc prolongation Dermatologic reactions Please see IMPORTANT SAFETY INFORMATION throughout and on page 7. Please see Table 2 in Section 2.3 of the full Prescribing Information for MEKTOVI for more information on adverse reactions that may require a dose adjustment or modification, such as: Venous thromboembolism Retinal vein occlusion (RVO) Interstitial lung disease, including pneumonitis Dermatologic reactions

6 Supporting patients through financial and access assistance for patients with BRAF-mutant metastatic melanoma 1,2 BRAFTOVI (encorafenib) + MEKTOVI (binimetinib) is available through the following specialty pharmacies To utilize the Array network of specialty pharmacies, please send your patient s prescription to one of the specialty pharmacies listed below Avella Specialty Pharmacy Diplomat Biologics Onco360 Oncology Pharmacy US Bioservices Supporting your patients starting on BRAFTOVI + MEKTOVI To help your patients start and stay on therapy, helpful resources can be found in the BRAFTOVI + MEKTOVI Patient Starter Kit. Array BioPharma does not influence or advocate for the use of any one specialty pharmacy and makes no representation or guarantee of services or coverage of any product. In-office dispensing may be available. Speak with your Array BioPharma representative or account manager to learn more. Eligible, commercially-insured patients may pay as little as $0 per month for BRAFTOVI + MEKTOVI The Co-Pay Savings Program* Eligible patients may pay as little as $0 per month supply of BRAFTOVI + MEKTOVI. Activation is simple on the online portal, with no income requirements * In order to be eligible for the Array Co-Pay Savings Program, the patient must not have government-funded health insurance (eg, Medicare, Medicaid, or any other federal or state program), must be taking BRAFTOVI + MEKTOVI for an FDA-approved indication, and confirm that they meet all of the eligibility criteria and agree to the rules set forth in the terms and conditions for the program. Please visit braftovimektovi.com for the full terms and conditions. Patient Starter Kit We are committed to helping patients access our medicines, regardless of their insurance coverage Array ACTS provides a range of financial and access support services to eligible patients, including Benefits investigation and verification Prior authorization and appeals support Patients must meet eligibility criteria. Patients and healthcare providers are responsible for completing and submitting enrollment forms and coverage or reimbursement documentation. Array makes no representation or guarantee concerning coverage or reimbursement of any service or item. This kit contains the following resources to help your BRAFTOVI + MEKTOVI patient during treatment: Welcome Letter BRAFTOVI + MEKTOVI Treatment Guide Treatment Journal and Calendar Two Daily Pill Trackers, one for each bottle of BRAFTOVI (green tracker) and MEKTOVI (burgundy tracker) Two No one fights alone wristbands, one for your patients and one for your patients caregivers Zippered Bag, designed to keep all your patients treatment-related materials in one place BRAFTOVI + MEKTOVI Drug Information Card SUPPORT For more information on Array ACTS and all the available assistance programs, please call ARRAYCS ( ). For more patient resources, as well as additional information on BRAFTOVI + MEKTOVI, please refer your patients to Tovi2.com. 6 Please see IMPORTANT SAFETY INFORMATION throughout and on page 7.

7 IMPORTANT SAFETY INFORMATION INDICATIONS AND USAGE BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. IMPORTANT SAFETY INFORMATION The information below applies to the safety of the combination of BRAFTOVI and MEKTOVI unless otherwise noted. See full prescribing information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions. WARNINGS AND PRECAUTIONS New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur. In the COLUMBUS trial, cutaneous squamous cell carcinoma (cuscc), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients. Median time to first occurrence of cuscc/ka was 5.8 months. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies. Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI. Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. In the COLUMBUS trial, evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients. Assess LVEF by echocardiogram or MUGA scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment. The safety has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely. Venous Thromboembolism (VTE): In the COLUMBUS trial, VTE occurred in 6% of patients, including 3.1% of patients who developed pulmonary embolism. Hemorrhage: In the COLUMBUS trial, hemorrhage occurred in 19% of patients and Grade 3 hemorrhage occurred in 3.2% of patients. Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Ocular Toxicities: In the COLUMBUS trial, serous retinopathy occurred in 20% of patients; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months. In patients with BRAF mutation-positive melanoma across multiple clinical trials, 0.1% of patients experienced retinal vein occlusion (RVO). Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO. In COLUMBUS, uveitis, including iritis and iridocyclitis was reported in 4% of patients. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals any time a patient reports visual disturbances. Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% of patients with BRAF mutation-positive melanoma across multiple clinical trials. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Hepatotoxicity: In the COLUMBUS trial, the incidence of Grade 3 or 4 increases in liver function laboratory tests was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Rhabdomyolysis: In the COLUMBUS trial, elevation of laboratory values of serum CPK occurred in 58% of patients. Rhabdomyolysis was reported in 0.1% of patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib across multiple clinical trials. Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. QTc Prolongation: In the COLUMBUS trial, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms. Embryo-Fetal Toxicity: BRAFTOVI or MEKTOVI can cause fetal harm when administered to pregnant women. Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI. Risks Associated with BRAFTOVI as a Single Agent: There is an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with MEKTOVI. Grades 3 or 4 dermatologic reactions occurred in 21% of BRAFTOVI single agent compared to 2% in patients treated with BRAFTOVI in combination with MEKTOVI. If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended. ADVERSE REACTIONS The most common adverse reactions ( 20%, all Grades, in the COLUMBUS trial): were fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), arthralgia (26%), myopathy (23%), hyperkeratosis (23%), rash (22%), headache (22%), constipation (22%), visual impairment (20%), serous retinopathy (20%). Other clinically important adverse reactions occurring in <10% of patients in the COLUMBUS Trial were facial paresis, pancreatitis, panniculitis, drug hypersensitivity and colitis. In the COLUMBUS Trial, the most common laboratory abnormalities (all grades) ( 20%) included increased creatinine (93%), increased creatine phosphokinase (58%), increased gamma glutamyl transferase (GGT) (45%), anemia (36%), increased ALT (29%), hyperglycemia (28%), increased AST (27%), and increased alkaline phosphatase (21%). DRUG INTERACTIONS Avoid concomitant use of strong or moderate CYP3A4 inhibitors or inducers and sensitive CYP3A4 substrates with BRAFTOVI. Modify BRAFTOVI dose if concomitant use of strong or moderate CYP3A4 inhibitors cannot be avoided. Please see accompanying full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information. References: 1. Braftovi (encorafenib) Prescribing Information. Boulder, CO: Array BioPharma Inc, 06/ Mektovi (binimetinib) Prescribing Information. Boulder, CO: Array BioPharma Inc, 06/ Data on file. Array BioPharma, Inc. 7

8 SUPPORTING YOUR PATIENTS THROUGH THEIR TREATMENT WITH BRAFTOVI TM (encorafenib) + MEKTOVI (binimetinib) 1,2 May be taken with or without food No refrigeration requirement; store at room temperature 5% of patients permanently discontinued treatment due to ARs The most common adverse reactions ( 25%) for BRAFTOVI + MEKTOVI were fatigue (43%), nausea (41%), diarrhea (36%), vomiting (30%), abdominal pain (28%), and arthralgia (26%) BRAFTOVI + MEKTOVI showed low rates of Grade 3/4 hypertension (6%), pyrexia (4%), arthralgia (1%), and rash (1%) Uninterrupted dosing schedule $0 Co-pay is available for eligible commerciallyinsured patients* * In order to be eligible for the Array Co-Pay Savings Program, the patient must not have governmentfunded health insurance, must be taking BRAFTOVI + MEKTOVI for an FDA-approved indication, and confirm that they meet all of the eligibility criteria and agree to the rules set forth in the terms and conditions for the program. Please visit braftovimektovi.com for the full terms and conditions. Please see IMPORTANT SAFETY INFORMATION throughout and on page 7, and accompanying full Prescribing Information for BRAFTOVI and full Prescribing Information for MEKTOVI for additional information Array BioPharma, Inc. All rights reserved. BRAFTOVI is a trademark of Array BioPharma, Inc. MEKTOVI is a registered trademark of Array BioPharma, Inc. in the United States and various other countries. PM-US-BIN+ENC /18 v1

9 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use BRAFTOVI safely and effectively. See full prescribing information for BRAFTOVI. BRAFTOVI (encorafenib) capsules, for oral use Initial U.S. Approval: INDICATIONS AND USAGE BRAFTOVI is a kinase inhibitor indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. (1, 2.1) Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma. (1, 5.2) DOSAGE AND ADMINISTRATION Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of BRAFTOVI. (2.1) The recommended dose is 450 mg orally once daily in combination with binimetinib. Take BRAFTOVI with or without food. (2.2) DOSAGE FORMS AND STRENGTHS Capsules: 50 mg and 75 mg. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS New Primary Malignancies, cutaneous and non-cutaneous: Can occur. Monitor for malignancies and perform dermatologic evaluations prior to, while on therapy, and following discontinuation of treatment. (5.1) Tumor Promotion in BRAF Wild-Type Tumors: Increased cell proliferation can occur with BRAF inhibitors. (5.2) Hemorrhage: Major hemorrhagic events can occur. (5.3) Uveitis: Perform ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.4) QT Prolongation: Monitor electrolytes before and during treatment. Correct electrolyte abnormalities and control for cardiac risk factors for QT prolongation. Withhold BRAFTOVI for QTc of 500 ms or greater. (5.5) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective non-hormonal method of contraception. (5.6, 8.1, 8.3) ADVERSE REACTIONS Most common adverse reactions (>25%) for BRAFTOVI, in combination with binimetinib, are fatigue, nausea, vomiting, abdominal pain, and arthralgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Array BioPharma at or FDA at FDA-1088 or DRUG INTERACTIONS Strong or moderate CYP3A4 inhibitors: Concomitant use may increase encorafenib plasma concentration. If concomitant use cannot be avoided, modify BRAFTOVI dose. (2.4, 7.1) Strong or moderate CYP3A4 inducers: Concomitant use may decrease encorafenib plasma concentrations. Avoid concomitant use. (7.1) Sensitive CYP3A4 substrates: Concomitant use with BRAFTOVI may increase toxicity or decrease efficacy of these agents. Avoid hormonal contraceptives. (7.2) USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) Males of Reproductive Potential: BRAFTOVI may impair fertility. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 01/2019 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Dosage Modifications for Adverse Reactions 2.4 Dose Modifications for Coadministration of Strong or Moderate CYP3A4 Inhibitors 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies 5.2 Tumor Promotion in BRAF Wild-Type Tumors 5.3 Hemorrhage 5.4 Uveitis 5.5 QT Prolongation 5.6 Embryo-Fetal Toxicity 5.7 Risks Associated with BRAFTOVI as a Single Agent 5.8 Risks Associated with Combination Treatment 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 7.1 Effect of Other Drugs on BRAFTOVI 7.2 Effect of BRAFTOVI on Other Drugs 7.3 Drugs That Prolong the QT Interval 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID:

10 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BRAFTOVI is indicated, in combination with binimetinib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)]. Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating BRAFTOVI [see Warnings and Precautions (5.2), Clinical Studies (14)]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: Recommended Dosage The recommended dosage of BRAFTOVI is 450 mg orally taken once daily in combination with binimetinib until disease progression or unacceptable toxicity. Refer to the binimetinib prescribing information for recommended binimetinib dosing information. BRAFTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take a missed dose of BRAFTOVI within 12 hours of the next dose of BRAFTOVI. Do not take an additional dose if vomiting occurs after BRAFTOVI administration but continue with the next scheduled dose. 2.3 Dosage Modifications for Adverse Reactions If binimetinib is withheld, reduce BRAFTOVI to a maximum dose of 300 mg once daily until binimetinib is resumed [see Warnings and Precautions (5.7)]. Dose reductions for adverse reactions associated with BRAFTOVI are presented in Table 1. Table 1: Recommended Dose Reductions for BRAFTOVI for Adverse Reactions Action Recommended Dose First Dose Reduction 300 mg orally once daily Second Dose Reduction 200 mg orally once daily Subsequent Modification Permanently discontinue if unable to tolerate BRAFTOVI 200 mg once daily Dosage modifications for adverse reactions associated with BRAFTOVI are presented in Table 2. 2 Reference ID:

11 Table 2: Recommended Dosage Modifications for BRAFTOVI for Adverse Reactions Severity of Adverse Reaction a Dose Modification for BRAFTOVI New Primary Malignancies [see Warnings and Precautions (5.1)] Non-Cutaneous RAS Mutation-positive Malignancies Uveitis [see Warnings and Precautions (5.4)] Permanently discontinue BRAFTOVI. Grade 1-3 If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold BRAFTOVI for up to 6 weeks. If improved, resume at same or reduced dose. If not improved, permanently discontinue BRAFTOVI. Grade 4 Permanently discontinue BRAFTOVI. QTc Prolongation [see Warnings and Precautions (5.5)] QTcF greater than 500 ms and less than or equal to 60 ms increase from baseline QTcF greater than 500 ms and greater than 60 ms increase from baseline Hepatotoxicity Grade 2 AST or ALT increased Grade 3 or 4 AST or ALT increased Dermatologic Withhold BRAFTOVI until QTcF less than or equal to 500 ms. Resume at reduced dose. If more than one recurrence, permanently discontinue BRAFTOVI. Permanently discontinue BRAFTOVI. Maintain BRAFTOVI dose. If no improvement within 4 weeks, withhold BRAFTOVI until improves to Grade 0-1 or to pretreatment/baseline levels and then resume at same dose. See Other Adverse Reactions. Grade 2 If no improvement within 2 weeks, withhold BRAFTOVI until Grade 0-1. Resume at same dose. Grade 3 Withhold BRAFTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. Grade 4 Permanently discontinue BRAFTOVI. Other Adverse Reactions (including Hemorrhage [see Warnings and Precautions (5.3)]) b a b Recurrent Grade 2 or First occurrence of any Grade 3 Withhold BRAFTOVI for up to 4 weeks. If improves to Grade 0-1 or to pretreatment/baseline level, resume at reduced dose. If no improvement, permanently discontinue BRAFTOVI. First occurrence of any Grade 4 Permanently discontinue BRAFTOVI or Withhold BRAFTOVI for up to 4 weeks. If improves to Grade 0-1 or to pretreatment/baseline level, then resume at reduced dose. If no improvement, permanently discontinue BRAFTOVI. Recurrent Grade 3 Consider permanently discontinuing BRAFTOVI. Recurrent Grade 4 Permanently discontinue BRAFTOVI. National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version Dose modification of BRAFTOVI when administered with binimetinib is not recommended for new primary cutaneous malignancies; ocular events other than uveitis, iritis, and iridocyclitis; interstitial lung disease/pneumonitis; cardiac dysfunction; creatine phosphokinase (CPK) elevation; rhabdomyolysis; and venous thromboembolism. Refer to the binimetinib prescribing information for dose modifications for adverse reactions associated with binimetinib. 3 Reference ID:

12 2.4 Dose Modifications for Coadministration of Strong or Moderate CYP3A4 Inhibitors Avoid concurrent use of strong or moderate CYP3A4 inhibitors during treatment with BRAFTOVI. If concomitant use of a strong or moderate CYP3A4 inhibitor is unavoidable, reduce the BRAFTOVI dose to one-third of the BRAFTOVI dose prior to concurrent use of strong CYP3A4 inhibitors or one-half of the BRAFTOVI dose prior to concurrent use of moderate CYP3A4 inhibitors. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the BRAFTOVI dose that was taken prior to initiating the CYP3A4 inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Capsules, hard gelatin: 50 mg: stylized A on orange cap and LGX 50mg on beige body 75 mg: stylized A on beige cap and LGX 75mg on white body 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 New Primary Malignancies New primary malignancies, cutaneous and non-cutaneous, have been observed in patients treated with BRAF inhibitors and can occur with BRAFTOVI. Cutaneous Malignancies In COLUMBUS, cutaneous squamous cell carcinoma (cuscc), including keratoacanthoma (KA), occurred in 2.6%, and basal cell carcinoma occurred in 1.6% of patients who received BRAFTOVI in combination with binimetinib. Median time to first occurrence of cuscc/ka was 5.8 months (range 1 to 9 months) [see Adverse Reactions (6.1)]. For patients who received BRAFTOVI as a single agent, cuscc/ka was reported in 8%, basal cell carcinoma in 1%, and a new primary melanoma in 5% of patients. Perform dermatologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation. Dose modification is not recommended for new primary cutaneous malignancies. Non-Cutaneous Malignancies Based on its mechanism of action, BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms [see Warnings and Precautions (5.2)]. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies [see Dosage and Administration (2.3)]. 5.2 Tumor Promotion in BRAF Wild-Type Tumors In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells, which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation prior to initiating BRAFTOVI [see Indications and Usage (1), Dosage and Administration (2.1)]. 5.3 Hemorrhage Hemorrhage can occur when BRAFTOVI is administered in combination with binimetinib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving BRAFTOVI in combination with binimetinib; Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. 4 Reference ID:

13 Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.4 Uveitis Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI in combination with binimetinib. In COLUMBUS, the incidence of uveitis among patients treated with BRAFTOVI in combination with binimetinib was 4%. Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.5 QT Prolongation BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients [see Clinical Pharmacology (12.2)]. In COLUMBUS, an increase in QTcF to > 500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with binimetinib. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation. Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc > 500 ms [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.6 Embryo-Fetal Toxicity Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman. Encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the recommended dose of 450 mg, with no clear findings at lower doses. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use an effective, non-hormonal method of contraception since BRAFTOVI can render hormonal contraceptives ineffective, during treatment and for 2 weeks after the final dose of BRAFTOVI [see Use in Specific Populations (8.1, 8.3)]. 5.7 Risks Associated with BRAFTOVI as a Single Agent BRAFTOVI when used as a single agent is associated with an increased risk of certain adverse reactions compared to when BRAFTOVI is used in combination with binimetinib. Grades 3 or 4 dermatologic reactions occurred in 21% of patients treated with BRAFTOVI single agent compared to 2% of patients treated with BRAFTOVI in combination with binimetinib [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. If binimetinib is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended [see Dosage and Administration (2.3)]. 5.8 Risks Associated with Combination Treatment BRAFTOVI is indicated for use in combination with binimetinib. Refer to the binimetinib prescribing information for additional risk information that applies to combination use treatment. 6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: New Primary Malignancies [see Warnings and Precautions (5.1)] Hemorrhage [see Warnings and Precautions (5.3)] Uveitis [see Warnings and Precautions (5.4)] QT Prolongation [see Warnings and Precautions (5.5)] 5 Reference ID:

14 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of BRAFTOVI in combination with binimetinib is described in 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma who received BRAFTOVI (450 mg once daily) in combination with binimetinib (45 mg twice daily) in a randomized open-label, active-controlled trial (COLUMBUS). The COLUMBUS trial [see Clinical Studies (14)] excluded patients with a history of Gilbert s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (>480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with BRAFTOVI in combination with binimetinib and 6.2 months for patients treated with vemurafenib. The most common (> 25%) adverse reactions in patients receiving BRAFTOVI in combination with binimetinib were fatigue, nausea, vomiting, abdominal pain, and arthralgia. Adverse reactions leading to dose interruptions of BRAFTOVI occurred in 30% of patients receiving BRAFTOVI in combination with binimetinib; the most common were nausea (7%), vomiting (7%) and pyrexia (4%). Adverse reactions leading to dose reductions of BRAFTOVI occurred in 14% of patients receiving BRAFTOVI in combination with binimetinib; the most common were arthralgia (2%), fatigue (2%) and nausea (2%). Five percent (5%) of patients receiving BRAFTOVI in combination with binimetinib experienced an adverse reaction that resulted in permanent discontinuation of BRAFTOVI; the most common were hemorrhage in 2% and headache in 1% of patients. Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for BRAFTOVI in combination with binimetinib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3. 6 Reference ID:

15 Table 3: Adverse Reactions Occurring in 10% of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS a Adverse Reaction All Grades (%) General Disorders and Administration Site Conditions BRAFTOVI with binimetinib N=192 Grades 3 and 4 b (%) All Grades (%) Vemurafenib N=186 Fatigue c Pyrexia c Gastrointestinal Disorders Nausea Vomiting c Abdominal pain c Constipation Musculoskeletal and Connective Tissue Disorders Arthralgia c Myopathy c Pain in extremity Grades 3 and 4 (%) Skin and Subcutaneous Tissue Disorders Hyperkeratosis c Rash c Dry skin c Alopecia c Pruritus c Nervous System Disorders Headache c Dizziness c Peripheral neuropathy c Vascular Disorders Hemorrhage c a b c Grades per National Cancer Institute CTCAE v4.03. Grade 4 adverse reactions limited to fatigue (n=1), pruritus (n=1) and rash (n=1) in the BRAFTOVI with binimetinib arm. Represents a composite of multiple, related preferred terms. BRAFTOVI when used as a single agent increases the risk of certain adverse reactions compared to BRAFTOVI in combination with binimetinib. In patients receiving BRAFTOVI 300 mg orally once daily as a single agent, the following adverse reactions were observed at a higher rate ( 5%) compared to patients receiving BRAFTOVI in combination with binimetinib: palmar-plantar erythrodysesthesia syndrome (51% vs. 7%), hyperkeratosis (57% vs. 23%), dry skin (38% vs. 16%), erythema (16% vs. 7%), rash (41% vs. 22%), alopecia (56% vs. 14%), pruritus (31% vs. 13%), arthralgia (44% vs. 26%), myopathy (33% vs. 23%), back pain (15% vs. 9%), dysgeusia (13% vs. 6%), and acneiform dermatitis (8% vs. 3%). 7 Reference ID:

16 Other clinically important adverse reactions occurring in < 10% of patients who received BRAFTOVI in combination with binimetinib were: Nervous system disorders: Facial paresis Gastrointestinal disorders: Pancreatitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity Table 4: Hematology Laboratory Abnormalities Occurring in 10% (All Grades) of Patients Receiving BRAFTOVI in Combination with Binimetinib in COLUMBUS a Laboratory Abnormality BRAFTOVI with binimetinib N=192 All Grades (%) Grades 3 and 4 (%) All Grades (%) Vemurafenib N=186 Grades 3 and 4 (%) Anemia Leukopenia Lymphopenia Neutropenia Chemistry a Increased Creatinine Increased Gamma Glutamyl Transferase Increased ALT Increased AST Hyperglycemia Increased Alkaline Phosphatase Hyponatremia Hypermagnesemia Grades per National Cancer Institute CTCAE v DRUG INTERACTIONS 7.1 Effect of Other Drugs on BRAFTOVI Strong or Moderate CYP3A4 Inhibitors Concomitant administration of BRAFTOVI with a strong or moderate CYP3A4 inhibitor increased encorafenib plasma concentrations and may increase encorafenib adverse reactions [see Clinical Pharmacology (12.3)]. Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors, including grapefruit juice. If coadministration of strong or moderate CYP3A4 inhibitors cannot be avoided, modify dose as recommended [see Dosage and Administration (2.4)]. Strong or Moderate CYP3A4 Inducers Concomitant administration of BRAFTOVI with a strong or moderate CYP3A4 inducer may decrease encorafenib plasma concentrations and may decrease encorafenib efficacy [see Clinical Pharmacology (12.3)]. Avoid concomitant administration of strong or moderate CYP3A4 inducers with BRAFTOVI. 8 Reference ID:

17 7.2 Effect of BRAFTOVI on Other Drugs Sensitive CYP3A4 Substrates Concomitant administration of BRAFTOVI with sensitive CYP3A4 substrates may result in increased toxicity or decreased efficacy of these agents. Coadministration of BRAFTOVI with hormonal contraceptives (CYP3A4 substrates) can result in decreased concentrations and loss of hormonal contraceptive efficacy. Avoid hormonal contraceptives [see Use in Specific Populations (8.3)]. 7.3 Drugs That Prolong the QT Interval BRAFTOVI is associated with dose-dependent QTc interval prolongation. Avoid coadministration of BRAFTOVI with medicinal products with a known potential to prolong QT/QTc interval [see Warnings and Precautions (5.5), Clinical Pharmacology (12.2)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on its mechanism of action, BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of BRAFTOVI during pregnancy. In animal reproduction studies, encorafenib produced embryo-fetal developmental changes in rats and rabbits and was an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 26 (in the rat) and 178 (in the rabbit) times the human exposure at the clinical dose of 450 mg, with no clear findings at lower doses (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicity studies, administration of encorafenib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights, and increased incidence of total skeletal variations at a dose of 20 mg/kg/day (approximately 26 times the human exposure based on area under the concentrationtime curve [AUC] at the recommended clinical dose of 450 mg once daily). In pregnant rabbits, administration of encorafenib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, increased incidence of total skeletal variations and increased post-implantation loss, including total loss of pregnancy at a dose of 75 mg/kg/day (approximately 178 times the human exposure based on AUC at the recommended clinical dose of 450 mg once daily). While formal placental transfer studies have not been performed, encorafenib exposure in the fetal plasma of both rats and rabbits was up to 1.7% and 0.8%, respectively, of maternal exposure. 8.2 Lactation Risk Summary There are no data on the presence of encorafenib or its metabolites in human milk or the effects of encorafenib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from BRAFTOVI in breastfed infants, advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating BRAFTOVI [see Use in Specific Populations (8.1)]. 9 Reference ID:

18 Contraception BRAFTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise females of reproductive potential to use effective contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Counsel patients to use a non-hormonal method of contraception since BRAFTOVI has the potential to render hormonal contraceptives ineffective [see Drug Interactions (7.2)]. Infertility Males Based on findings in male rats at doses approximately 13 times the human exposure at the 450 mg clinical dose, use of BRAFTOVI may impact fertility in males [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use The safety and effectiveness of BRAFTOVI have not been established in pediatric patients. 8.5 Geriatric Use Of the 690 patients with BRAF mutation-positive melanoma who received BRAFTOVI at doses between 300 mg and 600 mg once daily in combination with binimetinib (45 mg twice daily) across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of BRAFTOVI plus binimetinib were observed in elderly patients as compared to younger patients [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment Dose adjustment for BRAFTOVI is not recommended in patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3)]. A recommended dose has not been established for patients with moderate (Child-Pugh Class B) or severe (Child-Pugh Class C) hepatic impairment. 8.7 Renal Impairment No dose adjustment is recommended for patients with mild to moderate renal impairment (CLcr 30 to < 90 ml/min) [see Clinical Pharmacology (12.3)]. A recommended dose has not been established for patients with severe renal impairment (CLcr < 30 ml/min). 10 OVERDOSAGE Since encorafenib is 86% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with BRAFTOVI. 11 DESCRIPTION Encorafenib is a kinase inhibitor. The chemical name is methyl N-{(2S)-1-[(4-{3-[5-chloro-2-fluoro-3- (methanesulfonamido)phenyl]-1-(propan-2-yl)-1h-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2- yl}carbamate. The molecular formula is C 22 H 27 ClFN 7 O 4 S and the molecular weight is 540 daltons. The chemical structure of encorafenib is shown below: N Cl F H N S O O HN N N N O NH O 10 Reference ID:

19 Encorafenib is a white to almost white powder. In aqueous media, encorafenib is slightly soluble at ph 1, very slightly soluble at ph 2, and insoluble at ph 3 and higher. BRAFTOVI (encorafenib) capsules for oral use contain 50 mg or 75 mg of encorafenib with the following inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, magnesium stearate (vegetable origin). The capsule shell contains gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol). 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Encorafenib is a kinase inhibitor that targets BRAF V600E, as well as wild-type BRAF and CRAF in in vitro cell-free assays with IC 50 values of 0.35, 0.47, and 0.3 nm, respectively. Mutations in the BRAF gene, such as BRAF V600E, can result in constitutively activated BRAF kinases that may stimulate tumor cell growth. Encorafenib was also able to bind to other kinases in vitro including JNK1, JNK2, JNK3, LIMK1, LIMK2, MEK4, and STK36 and substantially reduce ligand binding to these kinases at clinically achievable concentrations ( 0.9 µm). Encorafenib inhibited in vitro growth of tumor cell lines expressing BRAF V600 E, D, and K mutations. In mice implanted with tumor cells expressing BRAF V600E, encorafenib induced tumor regressions associated with RAF/MEK/ERK pathway suppression. Encorafenib and binimetinib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared with either drug alone, co-administration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of encorafenib and binimetinib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone Pharmacodynamics Cardiac Electrophysiology A dedicated study to evaluate the QT prolongation potential of BRAFTOVI has not been conducted. BRAFTOVI is associated with dose-dependent QTc interval prolongation. Following administration of the recommended dose of BRAFTOVI in combination with binimetinib, based on a central tendency analysis of QTc in a study of adult patients with melanoma, the largest mean (90% CI) QTcF change from baseline (ΔQTcF) was 18 (14 to 22) ms [see Warnings and Precautions (5.5)] Pharmacokinetics The pharmacokinetics of encorafenib were studied in healthy subjects and patients with solid tumors, including advanced and unresectable or metastatic cutaneous melanoma harboring a BRAF V600E or V600K mutation. After a single dose, systemic exposure of encorafenib was dose proportional over the dose range of 50 mg to 700 mg. After once-daily dosing, systemic exposure of encorafenib was less than dose proportional over the dose range of 50 mg to 800 mg. Steady-state was reached within 15 days, with exposure being 50% lower compared to Day 1; intersubject variability (CV%) of AUC ranged from 12% to 69%. Absorption After oral administration, the median T max of encorafenib is 2 hours. At least 86% of the dose is absorbed. Effect of Food Administration of a single dose of BRAFTOVI 100 mg (0.2 times the recommended dose) with a high-fat, high-calorie meal (comprised of approximately 150 calories from protein, 350 calories from carbohydrates, and 500 calories from fat) decreased the mean maximum encorafenib concentration (Cmax) by 36% with no effect on AUC. 11 Reference ID:

20 Distribution Encorafenib is 86% bound to human plasma proteins in vitro. The blood-to-plasma concentration ratio is The geometric mean (CV%) of apparent volume of distribution is 164 L (70%). Elimination The mean (CV%) terminal half-life (t 1/2 ) of encorafenib is 3.5 hours (17%), and the apparent clearance is 14 L/h (54%) at day 1, increasing to 32 L/h (59%) at steady-state. Metabolism The primary metabolic pathway is N-dealkylation, with CYP3A4 as the main contributor (83%) to total oxidative clearance of encorafenib in human liver microsomes, followed by CYP2C19 (16%) and CYP2D6 (1%). Excretion Following a single oral dose of 100 mg radiolabeled encorafenib, 47% (5% unchanged) of the administered dose was recovered in the feces and 47% (2% unchanged) was recovered in the urine. Specific Populations Age (19 to 89 years), sex, body weight, mild hepatic impairment (Child-Pugh Class A), and mild or moderate renal impairment (CLcr 30 to < 90 ml/min) do not have a clinically meaningful effect on the pharmacokinetics of encorafenib. The effect of race or ethnicity, moderate or severe hepatic impairment (Child-Pugh Class B or C), and severe renal impairment (CLcr < 30 ml/min) on encorafenib pharmacokinetics have not been studied. Drug Interaction Studies Clinical Studies Effect of CYP3A4 Inhibitors on Encorafenib: Coadministration of a strong (posaconazole) or moderate (diltiazem) CYP3A4 inhibitor with BRAFTOVI increased the AUC of encorafenib by 3- and 2-fold, respectively, and increased the C max by 68% and 45%, respectively, after a single BRAFTOVI dose of 50 mg (0.1 times the recommended dose). Effect of CYP3A4 Inducers on Encorafenib: The effect of coadministration of a CYP3A4 inducer on encorafenib exposure has not been studied. In clinical trials, steady-state encorafenib exposures were lower than encorafenib exposures after the first dose, suggesting CYP3A4 auto-induction. Effect of Acid Reducing Agents on Encorafenib: Coadministration of a proton pump inhibitor, rabeprazole, had no effect on AUC and C max of encorafenib. Combination Treatment: Coadministration of BRAFTOVI (UGT1A1 inhibitor) with binimetinib (UGT1A1 substrate) had no effect on binimetinib exposure. In Vitro Studies Effect of Encorafenib on CYP/UGT Substrates: Encorafenib is a reversible inhibitor of UGT1A1, CYP1A2, CYP2B6, CYP2C8/9, CYP2D6, and CYP3A, and a time-dependent inhibitor of CYP3A4 at clinically relevant plasma concentrations. Encorafenib induced CYP2B6, CYP2C9, and CYP3A4 at clinically relevant plasma concentrations. Effect of Transporters on Encorafenib: Encorafenib is a substrate of P-glycoprotein (P-gp). Encorafenib is not a substrate of breast cancer resistance protein (BCRP), multidrug resistance-associated protein 2 (MRP2), organic anion transporting polypeptide (OATP1B1, OATP1B3) or organic cation transporter (OCT1) at clinically relevant plasma concentrations. Effect of Encorafenib on Transporters: Encorafenib inhibited P-gp, BCRP, OCT2, organic anion transporter (OAT1, OAT3), OATP1B1, and OATP1B3, but not OCT1 or MRP2 at clinically relevant plasma concentrations. 12 Reference ID:

21 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies with encorafenib have not been conducted. Encorafenib was not genotoxic in studies evaluating reverse mutations in bacteria, chromosomal aberrations in mammalian cells, or micronuclei in bone marrow of rats. No dedicated fertility studies were performed with encorafenib in animals. In a general toxicology study in rats, decreased testes and epididymis weights, tubular degeneration in testes, and oligospermia in epididymides were observed at doses approximately 13 times the human exposure at the 450 mg clinical dose based on AUC. No effects on reproductive organs were observed in either sex in any of the non-human primate toxicity studies Animal Toxicology and/or Pharmacology Adverse histopathology findings of hyperplasia and hyperkeratosis occurred in the stomach of rats at encorafenib doses of 20 mg/kg/day (approximately 14 times the human exposure at the 450 mg clinical dose based on AUC) or greater, in both 4 and 13-week studies. 14 CLINICAL STUDIES BRAFTOVI in combination with binimetinib was evaluated in a randomized, active-controlled, open-label, multicenter trial (COLUMBUS; NCT ). Eligible patients were required to have BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma, as detected using the biomerieux THxID BRAF assay. Patients were permitted to have received immunotherapy in the adjuvant setting and one prior line of immunotherapy for unresectable locally advanced or metastatic disease. Prior use of BRAF inhibitors or MEK inhibitors was prohibited. Randomization was stratified by American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c), Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1), and prior immunotherapy for unresectable or metastatic disease (yes versus no). Patients were randomized (1:1:1) to receive BRAFTOVI 450 mg once daily in combination with binimetinib 45 mg twice daily (BRAFTOVI in combination with binimetinib), BRAFTOVI 300 mg once daily, or vemurafenib 960 mg twice daily. Treatment continued until disease progression or unacceptable toxicity. Only the results of the approved dosing (BRAFTOVI 450 mg in combination with binimetinib 45 mg) are described below. The major efficacy outcome measure was progression-free survival (PFS), as assessed by a blinded independent central review, to compare BRAFTOVI in combination with binimetinib with vemurafenib. Additional efficacy outcome measures included overall survival (OS), as well as objective response rate (ORR) and duration of response (DoR) which were assessed by central review. A total of 577 patients were randomized, 192 to the BRAFTOVI in combination with binimetinib arm, 194 to the BRAFTOVI arm, and 191 to the vemurafenib arm. Of the 383 patients randomized to either the BRAFTOVI in combination with binimetinib or the vemurafenib arms, the median age was 56 years (20 to 89 years), 59% were male, 91% were White, and 72% had baseline ECOG performance status of 0. Ninetyfive percent (95%) had metastatic disease, 65% were Stage IVM1c, and 4% received prior CTLA-4, PD-1, or PD-L1 directed antibodies. Twenty-eight percent (28%) had elevated baseline serum lactate dehydrogenase (LDH), 45% had 3 organs with tumor involvement at baseline, and 3% had brain metastases. Based on centralized testing, 100% of patients tumors tested positive for BRAF mutations; BRAF V600E (88%), BRAF V600K (11%), or both (<1%). BRAFTOVI in combination with binimetinib demonstrated a statistically significant improvement in PFS compared to vemurafenib. Efficacy results are summarized in Table 5 and Figure 1. Table 5: Efficacy Results for COLUMBUS Progression-Free Survival BRAFTOVI with binimetinib N= Vemurafenib N=191 Reference ID:

22 BRAFTOVI with binimetinib N=192 Vemurafenib N=191 Number of events (%) 98 (51) 106 (55) Progressive disease 88 (46) 104 (54) Death 10 (5) 2 (1) Median PFS, months (95% CI) 14.9 (11, 18.5) 7.3 (5.6, 8.2) HR (95% CI) a 0.54 (0.41, 0.71) P-value b < Overall Survival c Number of events (%) 105 (55) 127 (67) Median OS, months (95% CI) 33.6 (22.4, 39.2) 16.9 (14.0, 24.5) HR (95% CI) a 0.61 (0.47, 0.79) Overall Response Rate ORR (95% CI) 63% (56%, 70%) 40% (33%, 48%) CR 8% 6% PR 55% 35% Duration of Response Median DoR, months (95% CI) 16.6 (12.2, 20.4) 12.3 (6.9, 16.9) CI = Confidence interval; CR = Complete response; DoR = Duration of response; HR = Hazard ratio; NE = Not estimable; ORR = Overall response rate; OS = Overall survival; PFS = Progression-free survival; PR = Partial response. a Estimated with Cox proportional hazard model adjusted by the following stratification factors: American Joint Committee on Cancer (AJCC) Stage (IIIB, IIIC, IVM1a or IVM1b, versus IVM1c) and Eastern Cooperative Oncology Group (ECOG) performance status (0 versus 1). b Log-rank test adjusted by the same stratification factors. c Based on a cutoff date 17.6 months after the date of the PFS analysis. Figure 1: Kaplan-Meier Curves for Progression-Free Survival in COLUMBUS 16 HOW SUPPLIED/STORAGE AND HANDLING BRAFTOVI (encorafenib) is supplied as 50 mg and 75 mg hard gelatin capsules. 14 Reference ID:

23 50 mg: stylized A on orange cap and LGX 50mg on beige body, available in cartons (NDC ) containing two bottles of 60 capsules each (NDC ). 75 mg: stylized A on beige cap and LGX 75mg on white body, available in cartons (NDC ) containing two bottles of 90 capsules each (NDC ). Store at 20 C to 25 C (68 F to 77 F); excursions permitted between 15 C and 30 C (59 F and 86 F) [see USP Controlled Room Temperature]. Do not use if safety seal under cap is broken or missing. Dispense in original bottle. Do not remove desiccant. Protect from moisture. Keep container tightly closed. 17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Inform patients of the following: New Primary Cutaneous Malignancies Advise patients to contact their healthcare provider immediately for change in or development of new skin lesions [see Warnings and Precautions (5.1)]. Hemorrhage Advise patients to notify their healthcare provider immediately with any symptoms suggestive of hemorrhage, such as unusual bleeding [see Warnings and Precautions (5.3)]. Uveitis Advise patients to contact their healthcare provider if they experience any changes in their vision [see Warnings and Precautions (5.4)]. QT Prolongation Advise patients that BRAFTOVI can cause QTc interval prolongation and to inform their physician if they have any QTc interval prolongation symptoms, such as syncope [see Warnings and Precautions (5.5)]. Females and Males of Reproductive Potential Embryo-Fetal Toxicity: Advise females with reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective non-hormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose. Advise females to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, during treatment with BRAFTOVI [see Warnings and Precautions (5.6), Use in Specific Populations (8.1)]. Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose [see Use in Specific Populations (8.2)]. Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility [see Use in Specific Populations (8.3)]. Strong or Moderate CYP3A Inducers or Inhibitors Coadministration of BRAFTOVI with a strong or moderate CYP3A inhibitor may increase encorafenib concentrations; while coadministration of BRAFTOVI with a strong or moderate CYP3A inducer may decrease encorafenib concentrations. Advise patients that they need to avoid certain medications while taking BRAFTOVI and to inform their healthcare provider of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit or grapefruit juice while taking BRAFTOVI [see Drug Interactions (7.1)]. Storage BRAFTOVI is moisture sensitive. Advise patients to store BRAFTOVI in the original bottle with desiccant and to keep the cap of the bottle tightly closed. Do not remove the desiccants from the bottle. 15 Reference ID:

24 Distributed by: Array BioPharma Inc Walnut Street Boulder, CO Array BioPharma Inc. All rights reserved. BRAFTOVI is a trademark of Array BioPharma Inc. Patented. See 16 Reference ID:

25 MEDICATION GUIDE BRAFTOVI (braf-toe-vee) (encorafenib) capsules Important information: If your healthcare provider prescribes BRAFTOVI with binimetinib, please read the Patient Information leaflet that comes with binimetinib. What is the most important information I should know about BRAFTOVI? BRAFTOVI may cause serious side effects, including: Risk of new skin cancers. BRAFTOVI when used alone, or with binimetinib, may cause skin cancers called cutaneous squamous cell carcinoma or basal cell carcinoma. Talk to your healthcare provider about your risk for these cancers. Check your skin and tell your healthcare provider right away about any skin changes, including a: o new wart o skin sore or reddish bump that bleeds or does not heal o change in size or color of a mole Your healthcare provider should check your skin before treatment with BRAFTOVI, every 2 months during treatment, and for up to 6 months after you stop treatment with BRAFTOVI to look for any new skin cancers. Your healthcare provider should also check for cancers that may not occur on the skin. Tell your healthcare provider about any new symptoms that develop during treatment with BRAFTOVI. See "What are the possible side effects of BRAFTOVI?" for more information about side effects. What is BRAFTOVI? BRAFTOVI is a prescription medicine used in combination with a medicine called binimetinib to treat people with a type of skin cancer called melanoma: that has spread to other parts of the body or cannot be removed by surgery, and that has a certain type of abnormal "BRAF" gene BRAFTOVI should not be used to treat people with wild-type BRAF melanoma. Your healthcare provider will perform a test to make sure that BRAFTOVI is right for you. It is not known if BRAFTOVI is safe and effective in children. Before taking BRAFTOVI, tell your healthcare provider about all of your medical conditions, including if you: o o have had bleeding problems have eye problems have heart problems, including a condition called long QT syndrome have been told that you have low blood levels of potassium, calcium, or magnesium have liver or kidney problems are pregnant or plan to become pregnant. BRAFTOVI can harm your unborn baby. Females who are able to become pregnant should use effective non-hormonal birth control (contraception) during treatment with BRAFTOVI and for 2 weeks after the final dose of BRAFTOVI. Birth control methods that contain hormones (such as birth control pills, injections or transdermal systems) may not work as well during treatment with BRAFTOVI. Talk to your healthcare provider about birth control methods that may be right for you during this time. o Your healthcare provider will do a pregnancy test before you start taking BRAFTOVI. Tell your healthcare provider right away if you become pregnant or think you might be pregnant during treatment with BRAFTOVI. are breastfeeding or plan to breastfeed. It is not known if BRAFTOVI passes into your breast milk. Do not breastfeed during treatment with BRAFTOVI and for 2 weeks after the final dose of BRAFTOVI. Talk to your healthcare provider about the best way to feed your baby during this time. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. BRAFTOVI and certain other medicines can affect each other, causing side effects or affecting how BRAFTOVI or the other medicines work. Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine. 1 NP-US-ENC /18 v1

26 How should I take BRAFTOVI? Take BRAFTOVI exactly as your healthcare provider tells you. Do not change your dose or stop taking BRAFTOVI unless your healthcare provider tells you to. Your healthcare provider may change your dose of BRAFTOVI, temporarily stop, or completely stop your treatment with BRAFTOVI if you develop certain side effects. Take BRAFTOVI in combination with binimetinib by mouth one time each day. BRAFTOVI may be taken with or without food. Avoid grapefruit during treatment with BRAFTOVI. Grapefruit products may increase the amount of BRAFTOVI in your body. If you miss a dose of BRAFTOVI, take it as soon as you remember. If it is within 12 hours of your next scheduled dose, take your next dose at your regular time. Do not make up for the missed dose. Do not take an extra dose if you vomit after taking your scheduled dose. Take your next dose at your regular time. If you stop treatment with binimetinib, talk to your healthcare provider about your BRAFTOVI treatment. Your BRAFTOVI dose may need to be changed. What are the possible side effects of BRAFTOVI? BRAFTOVI may cause serious side effects, including: See What is the most important information I should know about BRAFTOVI? Bleeding problems. BRAFTOVI, when taken with binimetinib, can cause serious bleeding problems, including in your stomach or brain, that can lead to death. Call your healthcare provider and get medical help right away if you have any signs of bleeding, including: o headaches, dizziness, or feeling weak o cough up blood or blood clots o vomit blood or your vomit looks like coffee grounds o red or black stools that look like tar Eye problems. Tell your healthcare provider right away if you develop any of these symptoms of eye problems: o o o o blurred vision, loss of vision, or other vision changes see colored dots see halos (blurred outline around objects) eye pain, swelling, or redness Changes in the electrical activity of your heart called QT prolongation. QT prolongation can cause irregular heartbeats that can be life threatening. Your healthcare provider should do tests before you start taking BRAFTOVI with binimetinib and during your treatment to check your body salts (electrolytes). Tell your healthcare provider right away if you feel faint, lightheaded, dizzy or if you feel your heart beating irregularly or fast while taking BRAFTOVI with binimetinib. These symptoms may be related to QT prolongation. The most common side effects of BRAFTOVI when taken with binimetinib, include: fatigue nausea vomiting abdominal pain pain or swelling of your joints BRAFTOVI may cause fertility problems in males. Talk to your healthcare provider if this is a concern for you. These are not all the possible side effects of BRAFTOVI. Call your doctor for medical advice about side effects. You may report side effects to FDA at FDA You may also report side effects to Array BioPharma Inc. at How should I store BRAFTOVI? Store BRAFTOVI at room temperature between 68 F to 77 F (20 C to 25 C). Store BRAFTOVI in the original bottle. Keep the BRAFTOVI bottle tightly closed and protect it from moisture. BRAFTOVI comes with a desiccant packet in the bottle to help protect your medicine from moisture. Do not remove the desiccant packet from the bottle. 2 NP-US-ENC /18 v1

27 Keep BRAFTOVI and all medicines out of the reach of children. General information about the safe and effective use of BRAFTOVI. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use BRAFTOVI for a condition for which it was not prescribed. Do not give BRAFTOVI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about BRAFTOVI that is written for health professionals. What are the ingredients in BRAFTOVI? Active ingredient: encorafenib Inactive ingredients: copovidone, poloxamer 188, microcrystalline cellulose, succinic acid, crospovidone, colloidal silicon dioxide, and magnesium stearate of vegetable origin Capsule shell: gelatin, titanium dioxide, iron oxide red, iron oxide yellow, ferrosoferric oxide, monogramming ink (pharmaceutical glaze, ferrosoferric oxide, propylene glycol) Distributed by: Array BioPharma Inc. Boulder, Colorado For more information, go to or call Array BioPharma Inc. All rights reserved. This Medication Guide has been approved by the U.S. Food and Drug Administration. Issued: June NP-US-ENC /18 v1

28 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use MEKTOVI safely and effectively. See full prescribing information for MEKTOVI. MEKTOVI (binimetinib) tablets, for oral use Initial U.S. Approval: INDICATIONS AND USAGE MEKTOVI is a kinase inhibitor indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test. (1, 2.1) DOSAGE AND ADMINISTRATION Confirm the presence of BRAF V600E or V600K mutation in tumor specimens prior to the initiation of MEKTOVI. (2.1) The recommended dose is 45 mg orally twice daily in combination with encorafenib. Take MEKTOVI with or without food. (2.2) For patients with moderate or severe hepatic impairment the recommended dose is 30 mg orally twice daily. (2.4, 8.6) DOSAGE FORMS AND STRENGTHS Tablets: 15 mg. (3) CONTRAINDICATIONS None. (4) WARNINGS AND PRECAUTIONS Cardiomyopathy: Assess left ventricular ejection fraction (LVEF) before initiating treatment, after one month of treatment, then every 2 to 3 months thereafter. The safety of MEKTOVI has not been established in patients with LVEF below 50%. (5.1) Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism can occur. (5.2) Ocular Toxicities: Serous retinopathy, retinal vein occlusion (RVO) and uveitis have occurred. Perform an ophthalmologic evaluation at regular intervals and for any visual disturbances. (5.3) Interstitial Lung Disease (ILD): Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. (5.4) Hepatotoxicity: Monitor liver function tests before and during treatment and as clinically indicated. (5.5) Rhabdomyolysis: Monitor creatine phosphokinase and creatinine periodically and as clinically indicated. (5.6) Hemorrhage: Major hemorrhagic events can occur. (5.7) Embryo-Fetal Toxicity: Can cause fetal harm. Advise females with reproductive potential of potential risk to the fetus and to use effective contraception. (5.8, 8.1, 8.3) ADVERSE REACTIONS Most common adverse reactions ( 25%) for MEKTOVI, in combination with encorafenib, are fatigue, nausea, diarrhea, vomiting, and abdominal pain. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Array BioPharma at or FDA at FDA-1088 or USE IN SPECIFIC POPULATIONS Lactation: Advise not to breastfeed. (8.2) See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 01/2019 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection 2.2 Recommended Dosage 2.3 Dosage Modifications for Adverse Reactions 2.4 Dosage Modifications for Moderate or Severe Hepatic Impairment 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy 5.2 Venous Thromboembolism 5.3 Ocular Toxicities 5.4 Interstitial Lung Disease 5.5 Hepatotoxicity 5.6 Rhabdomyolysis 5.7 Hemorrhage 5.8 Embryo-Fetal Toxicity 5.9 Risks Associated with Combination Treatment 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.3 Females and Males of Reproductive Potential 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION *Sections or subsections omitted from the full prescribing information are not listed. 1 Reference ID:

29 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE MEKTOVI is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test [see Dosage and Administration (2.1)]. 2 DOSAGE AND ADMINISTRATION 2.1 Patient Selection Confirm the presence of a BRAF V600E or V600K mutation in tumor specimens prior to initiating MEKTOVI [Clinical Studies (14)]. Information on FDA-approved tests for the detection of BRAF V600E and V600K mutations in melanoma is available at: Recommended Dosage The recommended dosage of MEKTOVI is 45 mg orally taken twice daily, approximately 12 hours apart, in combination with encorafenib until disease progression or unacceptable toxicity. Refer to the encorafenib prescribing information for recommended encorafenib dosing information. MEKTOVI may be taken with or without food [see Clinical Pharmacology (12.3)]. Do not take a missed dose of MEKTOVI within 6 hours of the next dose of MEKTOVI. Do not take an additional dose if vomiting occurs after MEKTOVI administration but continue with the next scheduled dose. 2.3 Dosage Modifications for Adverse Reactions If encorafenib is permanently discontinued, discontinue MEKTOVI. Dose reductions for adverse reactions associated with MEKTOVI are presented in Table 1. Table 1: Recommended Dose Reductions for MEKTOVI for Adverse Reactions Action Recommended Dose First Dose Reduction 30 mg orally twice daily Subsequent Modification Permanently discontinue if unable to tolerate MEKTOVI 30 mg orally twice daily Dosage modifications for adverse reactions associated with MEKTOVI are presented in Table 2. Table 2: Recommended Dosage Modifications for MEKTOVI for Adverse Reactions Severity of Adverse Reaction a Dose Modification for MEKTOVI Cardiomyopathy [see Warnings and Precautions (5.1)] Asymptomatic, absolute decrease in LVEF of greater than 10% from baseline that is also below lower limit of normal (LLN) Withhold MEKTOVI for up to 4 weeks, evaluate LVEF every 2 weeks. Resume MEKTOVI at a reduced dose if the following are present: LVEF is at or above the lower limit of normal and Absolute decrease from baseline is 10% or less and Patient is asymptomatic. If the LVEF does not recover within 4 weeks permanently discontinue MEKTOVI. Symptomatic congestive heart failure or Permanently discontinue MEKTOVI. absolute decrease in LVEF of greater than 20% from baseline that is also below LLN Venous Thromboembolism [see Warnings and Precautions (5.2)] Uncomplicated deep venous thrombosis (DVT) or pulmonary embolism (PE) Withhold MEKTOVI. If improves to Grade 0-1, resume at a reduced dose. If no improvement, permanently discontinue MEKTOVI. 2 Reference ID:

30 Severity of Adverse Reaction a Dose Modification for MEKTOVI Life threatening PE Permanently discontinue MEKTOVI. Serous Retinopathy [see Warnings and Precautions (5.3)] Symptomatic serous retinopathy/retinal pigment epithelial detachments Retinal Vein Occlusion (RVO) [see Warnings and Precautions (5.3)] Withhold MEKTOVI for up to 10 days. If improves and becomes asymptomatic, resume at same dose. If not improved, resume at a lower dose level or permanently discontinue MEKTOVI. Any Grade Permanently discontinue MEKTOVI. Uveitis [see Warnings and Precautions (5.3)] Grade 1-3 If Grade 1 or 2 does not respond to specific ocular therapy, or for Grade 3 uveitis, withhold MEKTOVI for up to 6 weeks. If improved, resume at same or reduced dose. If not improved, permanently discontinue MEKTOVI. Grade 4 Permanently discontinue MEKTOVI. Interstitial Lung Disease [see Warnings and Precautions (5.4)] Grade 2 Withhold MEKTOVI for up to 4 weeks. If improved to Grade 0-1, resume at a reduced dose. If not resolved within 4 weeks, permanently discontinue MEKTOVI. Grade 3 or Grade 4 Permanently discontinue MEKTOVI. Hepatotoxicity [see Warnings and Precautions (5.5)] Grade 2 AST or ALT increased Maintain MEKTOVI dose. If no improvement within 2 weeks, withhold MEKTOVI until improved to Grade 0-1 or to pretreatment/baseline levels and then resume at the same dose. Grade 3 or 4 AST or ALT increased See Other Adverse Reactions. Rhabdomyolysis or Creatine Phosphokinase (CPK) elevations [see Warnings and Precautions (5.6)] Grade 4 asymptomatic CPK elevation or Any Grade CPK elevation with symptoms or with renal impairment Dermatologic Withhold MEKTOVI dose for up to 4 weeks. If improved to Grade 0-1 resume at a reduced dose. If not resolved within 4 weeks, permanently discontinue MEKTOVI. Grade 2 If no improvement within 2 weeks, withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. Grade 3 Withhold MEKTOVI until Grade 0-1. Resume at same dose if first occurrence or reduce dose if recurrent. Grade 4 Permanently discontinue MEKTOVI. Other Adverse Reactions (including: Hemorrhage [see Warnings and Precautions (5.7)]) b Recurrent Grade 2 or First occurrence of any Grade 3 Withhold MEKTOVI for up to 4 weeks. If improves to Grade 0-1 or to pretreatment/baseline levels, resume at reduced dose. If no improvement, permanently discontinue MEKTOVI. First occurrence of any Grade 4 Permanently discontinue MEKTOVI, or Withhold MEKTOVI for up to 4 weeks. If improves to Grade 0-1 or to pretreatment/baseline levels, then resume at a reduced dose. If no improvement, permanently discontinue MEKTOVI. Recurrent Grade 3 Consider permanently discontinuing MEKTOVI. 3 Reference ID:

31 Severity of Adverse Reaction a Dose Modification for MEKTOVI Recurrent Grade 4 Permanently discontinue MEKTOVI. a b National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version Dose modification of MEKTOVI when administered with encorafenib is not recommended for the following adverse reactions: palmarplantar erythrodysesthesia syndrome (PPES), non-cutaneous RAS mutation-positive malignancies, and QTc prolongation. Refer to the encorafenib prescribing information for dose modifications for adverse reactions associated with encorafenib. 2.4 Dosage Modifications for Moderate or Severe Hepatic Impairment For patients with moderate (total bilirubin greater than 1.5 and less than or equal to 3 ULN and any AST) or severe (total bilirubin levels greater than 3 ULN and any AST) hepatic impairment, the recommended dosage is 30 mg orally taken twice daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. 3 DOSAGE FORMS AND STRENGTHS Tablets: 15 mg, yellow/dark yellow, unscored biconvex oval film-coated tablets debossed with a stylized A on one side and 15 on the other side. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Cardiomyopathy Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, evidence of cardiomyopathy (decrease in LVEF below the institutional LLN with an absolute decrease in LVEF 10% below baseline as detected by echocardiography or MUGA) occurred in 7% of patients receiving MEKTOVI plus encorafenib. Grade 3 left ventricular dysfunction occurred in 1.6% of patients. The median time to first occurrence of left ventricular dysfunction (any grade) in patients receiving MEKTOVI in combination with encorafenib was 3.6 months (range 0 to 21 months). Cardiomyopathy resolved in 87% of patients receiving MEKTOVI plus encorafenib. Assess ejection fraction by echocardiogram or MUGA scan prior to initiating treatment, one month after initiating treatment, and then every 2 to 3 months during treatment. The safety of MEKTOVI in combination with encorafenib has not been established in patients with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN). Patients with cardiovascular risk factors should be monitored closely when treated with MEKTOVI. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.2 Venous Thromboembolism In COLUMBUS, venous thromboembolism (VTE) occurred in 6% of patients receiving MEKTOVI in combination with encorafenib, including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 4 Reference ID:

32 5.3 Ocular Toxicities Serous Retinopathy In COLUMBUS, serous retinopathy occurred in 20% of patients treated with MEKTOVI in combination with encorafenib; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. No patient discontinued MEKTOVI due to serous retinopathy; 6% of patients required dose interruptions or dose reductions. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months (range 0 to 17.5 months). Assess for visual symptoms at each visit. Perform an ophthalmologic examination at regular intervals, for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. Retinal Vein Occlusion RVO is a known class-related adverse reaction of MEK inhibitors and may occur in patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 1 patient experienced RVO (0.1%). The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes. Perform ophthalmologic evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. Uveitis Uveitis, including iritis and iridocyclitis, has been reported in patients treated with MEKTOVI in combination with encorafenib. In COLUMBUS, the incidence of uveitis among patients treated with MEKTOVI in combination with encorafenib was 4%. Assess for visual symptoms at each visit. Perform an ophthalmologic evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.4 Interstitial Lung Disease In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), 2 patients (0.3%) developed interstitial lung disease (ILD), including pneumonitis. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.5 Hepatotoxicity Hepatotoxicity can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, the incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI in combination with encorafenib was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation. Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5 Reference ID:

33 5.6 Rhabdomyolysis Rhabdomyolysis can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, elevation of laboratory values of serum CPK occurred in 58% of patients treated with MEKTOVI in combination with encorafenib. In patients with BRAF mutation-positive melanoma receiving MEKTOVI with encorafenib (n=690), rhabdomyolysis was reported in 1 patient (0.1%). Monitor CPK and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.7 Hemorrhage Hemorrhage can occur when MEKTOVI is administered in combination with encorafenib. In COLUMBUS, hemorrhage occurred in 19% of patients receiving MEKTOVI in combination with encorafenib. Grade 3 or greater hemorrhage occurred in 3.2% of patients. The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction [see Dosage and Administration (2.3), Adverse Reactions (6.1)]. 5.8 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman. Binimetinib was embryotoxic and abortifacient when administered to rabbits during the period of organogenesis at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the recommended clinical dose of 45 mg twice daily. Advise women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose [see Use in Specific Populations (8.1, 8.3)]. 5.9 Risks Associated with Combination Treatment MEKTOVI is indicated for use in combination with encorafenib. Refer to the encorafenib prescribing information for additional risk information that applies to combination use treatment. 6 ADVERSE REACTIONS The following adverse reactions are described elsewhere in the labeling: Cardiomyopathy [see Warnings and Precautions (5.1)] Venous Thromboembolism [see Warnings and Precautions (5.2)] Ocular Toxicities [see Warnings and Precautions (5.3)] Interstitial Lung Disease [see Warnings and Precautions (5.4)] Hepatotoxicity [see Warnings and Precautions (5.5)] Rhabdomyolysis [see Warnings and Precautions (5.6)] Hemorrhage [see Warnings and Precautions (5.7)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described in Warnings and Precautions [see Warnings and Precautions (5)] reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in a randomized open-label, activecontrolled trial (COLUMBUS) or, for rare events, exposure of 690 patients with BRAF V600 mutation- 6 Reference ID:

34 positive melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials. The data described below reflect exposure of 192 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma to MEKTOVI (45 mg twice daily) in combination with encorafenib (450 mg once daily) in COLUMBUS. The COLUMBUS trial [see Clinical Studies (14)] excluded patients with a history of Gilbert s syndrome, abnormal left ventricular ejection fraction, prolonged QTc (> 480 msec), uncontrolled hypertension, and history or current evidence of retinal vein occlusion. The median duration of exposure was 11.8 months for patients treated with MEKTOVI in combination with encorafenib and 6.2 months for patients treated with vemurafenib. The most common ( 25%) adverse reactions in patients receiving MEKTOVI in combination with encorafenib were fatigue, nausea, diarrhea, vomiting, and abdominal pain. Adverse reactions leading to dose interruptions of MEKTOVI occurred in 33% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (6%) and serous retinopathy (5%). Adverse reactions leading to dose reductions of MEKTOVI occurred in 19% of patients receiving MEKTOVI in combination with encorafenib; the most common were left ventricular dysfunction (3%), serous retinopathy (3%), and colitis (2%). Five percent (5%) of patients receiving MEKTOVI in combination with encorafenib experienced an adverse reaction that resulted in permanent discontinuation of MEKTOVI. The most common adverse reactions resulting in permanent discontinuation of MEKTOVI were hemorrhage in 2% and headache in 1% of patients. Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities, respectively, identified in COLUMBUS. The COLUMBUS trial was not designed to demonstrate a statistically significant difference in adverse reaction rates for MEKTOVI in combination with encorafenib, as compared to vemurafenib, for any specific adverse reaction listed in Table 3. 7 Reference ID:

35 Table 3: Adverse Reactions Occurring in 10% of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS a Adverse Reaction MEKTOVI with encorafenib N=192 All Grades (%) General Disorders and Administration Site Conditions Grades 3 and 4 b (%) All Grades (%) Vemurafenib N=186 Fatigue c Pyrexia c Peripheral edema c Gastrointestinal Disorders Nausea Diarrhea Vomiting c Abdominal pain c Constipation Skin and Subcutaneous Tissue Disorders Grades 3 and 4 b (%) Rash c Nervous System Disorders Dizziness c Visual Disorders Visual impairment c Serous retinopathy/rped c Vascular Disorders a b c Hemorrhage c Hypertension c Grades per National Cancer Institute CTCAE v4.03. Grade 4 adverse reactions limited to diarrhea (n=1) and hemorrhage (n=3) in the MEKTOVI with encorafenib arm and constipation (n=1) in the vemurafenib arm. Represents a composite of multiple, related preferred terms. Other clinically important adverse reactions occurring in < 10% of patients who received MEKTOVI in combination with encorafenib were: Gastrointestinal disorders: Colitis Skin and subcutaneous tissue disorders: Panniculitis Immune system disorders: Drug hypersensitivity 8 Reference ID:

36 Table 4: Hematology Laboratory Abnormalities Occurring in 10% (All grades) of Patients Receiving MEKTOVI in Combination with Encorafenib in COLUMBUS a Laboratory Abnormality MEKTOVI with encorafenib N=192 All Grades (%) 9 Grades 3 and 4 (%) All Grades (%) Vemurafenib N=186 Grades 3 and 4 (%) Anemia Leukopenia Lymphopenia Neutropenia Chemistry a Increased Creatinine Increased Creatine Phosphokinase Increased Gamma Glutamyl Transferase Increased ALT Increased AST Increased Alkaline Phosphatase Hyponatremia Grades per National Cancer Institute CTCAE v DRUG INTERACTIONS No clinically important drug interactions have been observed with MEKTOVI. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Based on findings from animal reproduction studies and its mechanism of action, MEKTOVI can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available clinical data on the use of MEKTOVI during pregnancy. In animal reproduction studies, oral administration of binimetinib during the period of organogenesis was embryotoxic and an abortifacient in rabbits at doses greater than or equal to those resulting in exposures approximately 5 times the human exposure at the clinical dose of 45 mg twice daily (see Data). Advise pregnant women of the potential risk to a fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In reproductive toxicity studies, administration of binimetinib to rats during the period of organogenesis resulted in maternal toxicity, decreased fetal weights and increased variations in ossification at doses 30 mg/kg/day (approximately 37 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). In pregnant rabbits, administration of binimetinib during the period of organogenesis resulted in maternal toxicity, decreased fetal body weights, an increase in malformations, and increased post-implantation loss, including total loss of pregnancy at doses 10 mg/kg/day (approximately 5 times the human exposure based on AUC at the recommended clinical dose of 45 mg twice daily). There was a significant increase in fetal ventricular septal defects and pulmonary trunk alterations at 20 mg/kg/day Reference ID:

37 of binimetinib (less than 8 times the human exposure at the recommended clinical dose of 45 mg twice daily). 8.2 Lactation Risk Summary There are no data on the presence of binimetinib or its active metabolite in human milk, or the effects of binimetinib on the breastfed infant, or on milk production. Because of the potential for serious adverse reactions from MEKTOVI in breastfed infants, advise women not to breastfeed during treatment with MEKTOVI and for 3 days after the final dose. 8.3 Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to initiating MEKTOVI [see Use in Specific Populations (8.1)]. Contraception MEKTOVI can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)]. Females Advise females of reproductive potential to use effective contraception during treatment with MEKTOVI and for at least 30 days after the final dose. 8.4 Pediatric Use The safety and effectiveness of MEKTOVI have not been established in pediatric patients. 8.5 Geriatric Use Of the 690 patients with BRAF mutation-positive melanoma who received MEKTOVI (45 mg twice daily) in combination with encorafenib at doses between 300 mg and 600 mg once daily across multiple clinical trials, 20% were aged 65 to 74 years and 8% were aged 75 years and older. No overall differences in the safety or effectiveness of MEKTOVI plus encorafenib were observed in elderly patients as compared to younger patients [see Clinical Pharmacology (12.3)]. 8.6 Hepatic Impairment Binimetinib concentrations may increase in patients with moderate or severe hepatic impairment. Dose adjustment for MEKTOVI is not recommended in patients with mild hepatic impairment (total bilirubin > 1 and 1.5 ULN and any AST or total bilirubin ULN and AST > ULN). Reduce the dose of MEKTOVI for patients with moderate (total bilirubin > 1.5 and 3 ULN and any AST) or severe (total bilirubin levels > 3 ULN and any AST) hepatic impairment [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. 10 OVERDOSAGE Since binimetinib is 97% bound to plasma proteins, hemodialysis is likely to be ineffective in the treatment of overdose with MEKTOVI. 11 DESCRIPTION Binimetinib is a kinase inhibitor. The chemical name is 5-[(4-bromo-2-fluorophenyl)amino]-4-fluoro-N-(2- hydroxyethoxy)-1-methyl-1h-benzimidazole-6-carboxamide. The molecular formula is C 17 H 15 BrF 2 N 4 O 3 and the molecular weight is daltons. The chemical structure of binimetinib is shown below: 10 Reference ID:

38 Binimetinib is a white to slightly yellow powder. In aqueous media, binimetinib is slightly soluble at ph 1, very slightly soluble at ph 2, and practically insoluble at ph 4.5 and higher. MEKTOVI (binimetinib) tablets for oral use contain 15 mg of binimetinib with the following inactive ingredients: lactose monohydrate, microcrystalline cellulose, croscarmellose sodium, magnesium stearate (vegetable source), and colloidal silicon dioxide. The coating contains polyvinyl alcohol, polyethylene glycol, titanium dioxide, talc, ferric oxide yellow, and ferrosoferric oxide. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Binimetinib is a reversible inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway. In vitro, binimetinib inhibited extracellular signal-related kinase (ERK) phosphorylation in cellfree assays as well as viability and MEK-dependent phosphorylation of BRAF-mutant human melanoma cell lines. Binimetinib also inhibited in vivo ERK phosphorylation and tumor growth in BRAF-mutant murine xenograft models. Binimetinib and encorafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Compared to either drug alone, coadministration of encorafenib and binimetinib resulted in greater anti-proliferative activity in vitro in BRAF mutation-positive cell lines and greater anti-tumor activity with respect to tumor growth inhibition in BRAF V600E mutant human melanoma xenograft studies in mice. Additionally, the combination of binimetinib and encorafenib delayed the emergence of resistance in BRAF V600E mutant human melanoma xenografts in mice compared to either drug alone Pharmacodynamics Cardiac Electrophysiology Following MEKTOVI 45 mg twice daily, no clinically meaningful QT prolongation was observed Pharmacokinetics The pharmacokinetics of binimetinib was studied in healthy subjects and patients with solid tumors. After twice-daily dosing, the accumulation is 1.5-fold and the coefficient of variation (CV%) of the area under the concentration-time curve (AUC) is < 40% at steady state. The systemic exposure of binimetinib is approximately dose proportional. Absorption After oral administration, at least 50% of the binimetinib dose was absorbed with a median time to maximum concentration (T max ) of 1.6 hours. Effect of Food The administration of a single dose of MEKTOVI 45 mg with a high-fat, high-calorie meal (consisting of approximately 150 calories from protein, 350 calories from carbohydrate, and 500 calories from fat) in healthy subjects had no effect on binimetinib exposure. Distribution Binimetinib is 97% bound to human plasma proteins and the blood-to-plasma ratio is The geometric mean (CV%) of apparent volume of distribution of binimetinib is 92 L (45%). 11 Reference ID: